The pneumococcus remains the cause of meningitis with the greatest morbidity and mortality in children and older adults. This pattern persists despite the use of antibiotics of exceptionally rapid bactericidal activity. Over the past 10 years of this proposal we have sought to understand the biochemical basis of the inflammatory response to pneumococci in the subarachnoid space. We established that the pneumococcal cell wall is a library of inflammatory components which incites the cytokine, coagulation and arachidonate cascades and directly injures endothelial cells of the blood brain barrier. Further, we established that the release of cell wall during antibiotic-induced death engenders a dramatic host response that is responsible for serious injury to host tissues. This provided a rationale for use of agents like dexamethasone that can act as partner drugs with antibiotics to selectively control the injurious components of the host defense response. The current proposal seeks to determine the molecular details of the mechanism of pneumococcal invasion into brain and how neuronal cells are killed during meningitis. Blocking information decreases some sequelae of infection but does not appear to be sufficient in controlling neuronal loss, particularly for pneumococcal disease. Over half of the current survivors of this injection still have major permanent sequelae. Understanding this process will allow design of agents to specifically attenuate these ongoing losses. We propose to apply our expertise in the identification and characterization of pneumococcal surface components, to map the process of transcytosis across the blood brain barrier. We will identify the pneumococcal components involved, specifically focusing on CbpA. This protein is required for pneumococcal invasion. Secondly, we will characterize the process of pneumococcal translocation in terms of the intracellular vesicle and the signaling process. Involvement of the PAF receptor that binds pneumococci and sIgA that ligates CbpA in actual translocation will be determined. Finally, we will investigate preliminary evidence that upon inhibition of apoptosis suggest this is an important contributor to sequelae. The detailed mechanism appears to be novel and will potentially instruct cell biology as well as pathogenesis.